第 64 章大脑老化

如图 64.0.1 所示，在 1900 年，美国的平均寿命约为 50 岁。到 2015 年，男性约为 77 岁，女性约为 82 岁。其

他 30 个国家的平均水平更高。这些增加主要是由于婴儿死亡率的降低、疫苗和抗生素的开发、更好的营养、改

进的公共卫生措施以及心脏病和中风的治疗和预防方面的进步。由于预期寿命的延长，以及二战后不久出生的

大批“婴儿潮一代”，老年人成为美国人口中增长最快的部分。

1562 Part IX / Diseases of the Nervous System

Figure 64–1 The human life span is increas-

ing.The average life span in the United States

has increased rapidly over the past 100 years.

(Adapted from Strehler 1975; Arias 2004.)

signs of underlying alterations in the nervous system.

For example, as motor skills decline, posture becomes

less erect, gait is slower, stride length is shorter, and

postural reflexes often become sluggish. Although

muscles weaken and bones become more brittle, these

motor abnormalities result in large part from subtle

processes that involve the peripheral and central nerv-

ous systems. Sleep patterns also change with age; older

people sleep less and wake more frequently. Mental

functions ascribed to the forebrain, such as memory

and problem-solving abilities, also decline.

Age-related declines in mental abilities are highly

variable, in both rate and severity (Figure 64–2A).

Although most people experience a gradual decline in

mental agility, for some, the decline is rapid, whereas

others retain their cognitive powers throughout life—

Giuseppe Verdi, Eleanor Roosevelt, and Pablo Picasso

are well-known examples of the latter category. Titian

continued to paint masterpieces in his late 80s, and

Sophocles is said to have written Oedipus at Colonus in

his 92nd year. The fact that elderly people with com-

pletely preserved mental function are rare suggests

that there may be special properties in the life experi-

ences or genes of these people. Accordingly, there has

been great interest in studying individuals who retain

nearly intact cognition into their tenth or even eleventh

decade. These centenarians may provide insight into

environmental or genetic factors that protect against

normal age-related cognitive decline or the more

devastating pathological descent into dementia. One

protective gene variant, discussed below, is the epsilon

2 allele of the apolipoprotein E gene.

An interesting finding that has emerged from stud-

ies of many individuals is that some cognitive capacities

decline significantly with age while others are largely

spared (Figure 64–2B). For example, working and

long-term memories, visuospatial abilities (measured

by arranging blocks into a design or drawing a three-

dimensional figure), and verbal fluency (measured by

rapid naming of objects or naming as many words as

possible that start with a specific letter) usually decline

with old age. On the other hand, measures of vocabu-

lary, information, and comprehension often show mini-

mal decline in normal individuals well into the 80s.

Age-related changes in memory, motor activity,

mood, sleep pattern, appetite, and neuroendocrine

function result from alterations in the structure and

function of the brain. Even the healthiest 80-year-old

brain does not look like it did at the age of 20. Elderly

people exhibit mild shrinkage in the volume of the

brain and a loss in brain weight, as well as enlargement

of the cerebral ventricles (Figure 64–3A). The decreases

in brain weight average 0.2% per year from college age

onward, and about 0.5% per year in the 70s.

These changes could result from death of neurons.

Indeed, some neurons are lost with age. For example,

25% or more of the motor neurons that innervate

skeletal muscles die in generally healthy elderly indi-

viduals. As we will see, neurodegenerative diseases

such as Alzheimer disease markedly accelerate the

1900

19 世纪以前

10 20 30 40 50 60 70 80 90 10

100

1950 2002

存活百分比

年龄

Kandel-Ch64_1561-1582.indd 1562 19/01/21 9:21 AM

图 64.0.1: 人类的寿命正在增加。在过去的 100 年里，美国人的平均寿命增长迅速

[555-556]

。

寿命延长是一把双刃剑，因为与年龄相关的认知改变越来越普遍。变化的程度因人而异。对于许多人来说，

这些改变是温和的，对生活质量的影响相对较小，我们戏称这些短暂的失误称为“老年时刻”。其他认知障碍虽

然不会使人虚弱，但足以阻碍我们独立管理生活的能力。然而，痴呆症会侵蚀记忆和推理并改变人格。其中，阿

尔茨海默病最为普遍。

随着人口老龄化，神经科学家、神经学家和心理学家开始投入更多精力来了解大脑中与年龄相关的变化。主

要动机是寻找阿尔茨海默病和其他痴呆症的治疗方法，但了解认知能力随年龄下降的正常过程也很重要。毕竟，

年龄是各种神经退行性疾病的最大危险因素。了解随着年龄的增长我们的大脑会发生什么，不仅可以改善普通

人群的生活质量，还可以提供最终帮助我们克服看似无关的病理变化线索。

考虑到这一点，我们在本章开始考虑大脑的正常老化。然后我们转向广泛的认知病理变化，最后关注阿尔

茨海默病。

64.1 大脑的结构和功能随年龄变化

随着年龄的增长，我们的身体会发生变化：头发变薄，皮肤起皱，关节吱吱作响。因此，我们的大脑也会发

生变化也就不足为奇了。事实上，随着年龄的增长而发生的广泛行为改变是神经系统潜在改变的迹象。例如，随

着运动技能的下降，姿势变得不那么直立，步态变慢，步幅变短，姿势反射常常变得迟钝。尽管肌肉变弱并且骨

64.1 大脑的结构和功能随年龄变化

骼变得更脆，但这些运动异常在很大程度上由涉及周围神经系统和中枢神经系统的微妙过程引起。睡眠模式也

会随着年龄的增长而改变；老年人睡得更少，醒得更频繁。归因于前脑的心理功能（例如记忆力和解决问题的

能力）也会下降。

如图 64.1.1A 所示，与年龄相关的心智能力下降在速度和严重程度上变化很大。虽然大多数人的思维敏捷度

会逐渐下降，但对某些人来说，下降速度很快，而其他人则终生保持认知能力，朱塞佩 · 威尔第、埃莉诺 · 罗斯

福和巴勃罗 · 毕加索就是后一类的著名例子。提香在他 80 多岁时继续创作杰作，据说索福克勒斯在他 92 岁时创

作了《俄狄浦斯在科罗诺斯》。心理功能完好保存的老年人很少见，这表明这些人的生活经历或基因可能具有特

殊性质。因此，人们对研究在 10 岁甚至 11 岁时几乎保持完好认知的个体产生了极大的兴趣。这些百岁老人可

能会深入了解环境或遗传因素，这些因素可以防止正常的与年龄相关的认知衰退或更具破坏性的痴呆病理下降。

下面讨论的一种保护性基因变体是载脂蛋白 E 基因的 epsilon 2 等位基因。

Chapter 64 / The Aging Brain 1563

Figure 64–2 There is variation in age-related cognitive

decline.

A.Scores of three people who were given a battery of cogni-

tive tests annually for decades. Person A declined rapidly.

Persons B and C showed similar cognitive performances into

their 80s but then diverged. (Adapted from Rubin et al. 1998.)

B.Average scores on several cognitive tests administered

to a large number of people. Long-term declarative memory

and working memory decline throughout life and more so in

advanced age. In contrast, knowledge of vocabulary is main-

tained. (Adapted from Park et al. 1996.)

death of neurons (Figure 64–3B). In most parts of the

healthy brain, however, there is minimal to no neu-

ronal loss simply because of age, so brain shrinkage

must arise from other factors.

In fact, analysis of the brains of humans and exper-

imental animals reveals structural alterations in both

neurons and glia. Myelin is fragmented and lost, com-

promising the integrity of white matter. At the same

time, the density of the dendritic arbors of cortical

and other neurons decreases, resulting in shrinkage

of neuropil. Levels of enzymes that synthesize some

neurotransmitters, such as dopamine, norepinephrine,

and acetylcholine, decrease with age, and this decline

presumably results in functional defects in synapses

that use these transmitters. Synapse structure is also

altered, at least at the neuromuscular junction (Figure

64–4), raising the possibility that structural changes

also lead to functional deficits at central synapses.

Finally, the number of synapses in the neocortex and

many other regions of the brain declines (Figure 64–5).

These cellular changes interfere with the integrity

of the neural circuits that mediate our mental activi-

ties. Age-related loss of synapses along with impair-

ment in function of remaining synapses are thought

to be important contributors to cognitive decline.

Changes in white matter are widespread but are espe-

cially notable in the prefrontal and temporal cortex.

They may underlie alterations in executive functions

正则化分数

Normalized score

Number correct

1.0

0.5

0.6

0.4

0.2

–0.2

–0.4

–0.6

–0.8

–1.0

–0.5

–1.0

–1.5

20s

年龄十年

40s 60s 80s

20s 40s 60s 80s

20s40s 60s 80s

70 75 80 85 90 95

认知得分

年龄

个体 A

个体 B

A 个体差异性

B 任务变化

长时程记忆

工作记忆

词汇

个体 C

–4

–2

Kandel-Ch64_1561-1582.indd 1563 19/01/21 9:21 AM

图 64.1.1: 与年龄相关的认知衰退存在差异。A. 几十年来每年接受一系列认知测试的 3 个人的分数。人 A 迅速

下降。人 B 和 C 在 80 多岁时表现出相似的认知表现，但随后出现分歧

[557]

。B. 对大量人进行的多项认知测试的

平均分数。长期陈述性记忆和工作记忆在整个生命过程中都会下降，而且在高龄时更是如此。相反，词汇知识得

以保留

[558]

。

如图 64.1.1B 所示，从对许多人的研究中得出的一个有趣发现：一些认知能力会随着年龄的增长而显著下降，

而其他人则基本保持不变。例如，工作记忆和长期记忆、视觉空间能力（通过将积木排列到设计中或绘制三维图

形来衡量）和语言流畅性（通过快速命名对象或尽可能多地命名以特定字母开头的单词来衡量）通常随着年龄

的增长而下降。另一方面，词汇量、信息和理解力的衡量标准通常显示正常人在进入 80 年代后出现的轻微下降。

记忆力、运动活动、情绪、睡眠模式、食欲和神经内分泌功能的年龄相关变化是由大脑结构和功能的改变引

1378

64.2 相当一部分老年人的认知能力下降是显著的并且使人虚弱

起的。即使是最健康的 80 岁大脑看起来也不像 20 岁时那样。如图 64.1.2A 所示，老年人表现出大脑体积轻度萎

缩和脑重量减轻，以及脑室扩大。从大学时代开始，大脑重量平均每年减少 0.2%，70 岁每年约减少 0.5%。

这些变化可能是由神经元死亡引起的。事实上，一些神经元会随着年龄的增长而丢失。例如，25% 或更多

支配骨骼肌的运动神经元在一般健康的老年人中死亡。如图 64.1.2B 所示，正如我们将看到的，阿尔茨海默病等

神经退行性疾病会显著加速神经元的死亡。然而，在健康大脑的大部分区域，仅仅因为年龄的原因，神经元损失

很少甚至没有，所以大脑萎缩一定是由其他因素引起。

事实上，对人类和实验动物大脑的分析揭示了神经元和胶质细胞的结构改变。髓磷脂破碎和丢失，损害了

白质的完整性。同时，皮层和其他神经元的树突状分枝密度降低，导致神经细胞收缩。合成某些神经递质（如多

巴胺、去甲肾上腺素和乙酰胆碱）的酶水平会随着年龄的增长而下降，这种下降可能会导致使用这些递质的突

触出现功能缺陷。如图 64.1.3 所示，突触结构也发生了改变，至少在神经肌肉接头处是这样，增加了结构变化也

导致中枢突触功能缺陷的可能性。最后，如图 64.1.4 所示，新皮层和大脑许多其他区域的突触数量下降。

这些细胞变化会干扰调节我们心理活动的神经回路的完整性。与年龄相关的突触丧失以及剩余突触功能受

损被认为是导致认知能力下降的重要因素。白质的变化很普遍，但在前额叶皮层和颞叶皮层尤为显著。它们可能

是执行功能和集中注意力以及编码和存储记忆的能力改变的基础，这些功能位于额叶-纹状体系统和颞叶中。白

质的损失也可能有助于解释最近的发现，即老年人的大脑不太能够支持通常协同工作以进行复杂心理活动的广

泛分离区域的活动同步。这些大规模网络的中断可能是认知能力下降的重要原因。

长期以来，人们一直认为衰老是由于累积的遗传损伤或有毒废物导致细胞和组织逐渐退化的结果。支持这

一想法的发现是，从动物身上取出并置于组织培养皿中的有丝分裂细胞在衰老和死亡之前仅分裂有限次数。如

图 64.1.5 所示，这种“注定”衰老的观点在过去 10 到 20 年里发生了根本性的变化，这主要是由于在模式生物

中发现了显著延长寿命的突变。

这些戏剧性的发现表明：衰老过程是在活跃的基因控制下进行的。一种已被表征的调节通路包括胰岛素和

胰岛素样生长因子、它们的受体以及它们激活的信号传导程序。这些基因的破坏实际上增加了细胞对致命氧化

损伤的抵抗力。人们认为，这些基因的正常形式是通过进化选择的，因为它们在生殖期对生物体有益。它们对寿

命的不利影响，一旦动物过了繁殖年龄，可能是一个不幸的副作用，进化对此并不太关心。

这些发现对于理解衰老如何影响神经系统有 2 个主要意义。首先，导致或保护我们免受衰老破坏的生化机

制可能是导致神经元变化的因素，这些变化又导致了与年龄相关的认知衰退。目前，正在模型生物中开展研究

来探索细胞变化和认知功能之间的联系。其次，也许更令人兴奋的是，对基因研究发现途径的研究可以确定延

长寿命或健康寿命（一个人保持总体健康的时期）的药理学或环境策略。

迄今为止，延长寿命（从酵母到蠕虫再到灵长类动物）的最佳验证环境策略是限制热量摄入。热量限制似乎

是通过上述胰岛素通路中的基因起作用的，并且可能涉及一组称为乙酰化酶的酶。乙酰化酶被最初从红酒中分

离出来的化合物白藜芦醇激活。当给小鼠服用时，白藜芦醇反过来会延缓衰老的某些方面，包括认知能力下降。

虽然白藜芦醇不太可能成为人类的青春之泉，但它仍然是目前正在考虑的新化学物质的例证。这些化学策略不

仅使用模式生物探索导致衰老的积极因素，而且探索阻止模式生物（可能还有人类）在其整个生命周期中保持

总体健康的约束条件。

64.2 相当一部分老年人的认知能力下降是显著的并且使人虚弱

对于大多数人来说，与年龄相关的认知变化不会严重影响生活质量。然而，在一些老年人中，认知能力下降

达到了可以被视为病态的程度。在异常范围的低端是一系列称为轻度认知损伤的变化。这种综合症的特征是记

忆力减退，伴有其他认知障碍，这些障碍超出了正常衰老的范围。患有轻度认知损伤的人可能能够进行大多数

日常生活活动，尽管其他人会注意到这些损伤，并且通常会影响人进行某些对他们来说重要或愉快的活动的能

力，例如管理财务或玩文字游戏。

重要的是，轻度认知损伤是一种综合症，而不是一种诊断。许多潜在的问题，如抑郁症、过度用药、中风和

神经退行性疾病都可能导致轻度认知损伤。如图 64.2.1 所示，大约一半的轻度认知损伤患者患有潜在的阿尔茨

海默病，并且该组中超过 90% 的人将在轻度认知损伤诊断后的 5 年内发展为完全痴呆。如下所述，现在有生物

1379

64.2 相当一部分老年人的认知能力下降是显著的并且使人虚弱

1564 Part IX / Diseases of the Nervous System

Figure 64–3 Changes in brain

structure with age and at the onset

of Alzheimer disease.(Also see

Figure 64–8.)

A.Images of normal 22- and 89-year-

old brains reveal changes in the struc-

ture of the living brain. (Reproduced,

with permission, from R. Buckner.)

B.Images of the same individual

over a 4-year period illustrate the

progressive shrinking of cortical

structures and the beginning of

ventricular enlargement (red). These

structural changes are evident prior

to the onset of behavioral symptoms.

(Reproduced, with permission,

from N. Fox.)

and the ability to focus attention and encode and store

memory, functions that are localized in frontal-striatal

systems and the temporal lobes. The loss of white mat-

ter may also help explain the recent finding that the

elderly brain is less able to support synchronization

of activity in widely separated areas that normally

work together to carry out complex mental activities.

Disruption of these large-scale networks could be an

important cause of cognitive decline.

It was long thought that aging resulted from pro-

gressive deterioration of cells and tissues due to accu-

mulated genetic damage or toxic waste products. In

support of this idea was the finding that mitotic cells

removed from animals and placed in a tissue culture

dish divide only for a limited number of times before

they age and die. This view of “preordained” aging has

changed radically over the past 10 to 20 years, primarily

as a result of the discovery in model organisms of muta-

tions that significantly extend life span (Figure 64–6).

Such dramatic discoveries established that the

aging process is under active genetic control. One

such regulatory pathway that has been characterized

includes insulin and insulin-like growth factors, their

receptors, and the signaling programs they activate.

Disruption of these genes actually increases the resist-

ance of cells to lethal oxidative damage. It is thought

that the normal forms of these genes have been selected

through evolution because they benefit the organ-

ism during the reproductive period. Their deleterious

effects on longevity, once the animals are past repro-

ductive age, may be an unfortunate side effect about

which evolution cares little.

阿尔茨海默病的变化

无症状 45 岁

4 年后出现行为症状

A 年龄相关变化

正常

22 岁

正常 89

岁

Kandel-Ch64_1561-1582.indd 1564 19/01/21 9:21 AM

图 64.1.2: 随着年龄的增长和阿尔茨海默病的发作，大脑结构发生变化（另请参阅图 64.4.1）。A. 正常 22 岁和 89

岁大脑的图像揭示了活体大脑结构的变化。B. 同一个人在 4 年期间的图像显示皮层结构的逐渐收缩和心室扩大

的开始（红色）。这些结构变化在行为症状出现之前就很明显。

1380

64.2 相当一部分老年人的认知能力下降是显著的并且使人虚弱

Chapter 64 / The Aging Brain 1565

Figure 64–4 Age-related changes in dendritic and

synaptic structure.Cortical pyramidal neurons in

rodents lose dendritic spines with age. Neuromuscular

synapses in rodents also exhibit age-related changes in

structure. (Spine images reproduced, with permission,

from J. Luebke; synapse images reproduced, with per-

mission, from G. Valdez.)

Figure 64–5 Age-related changes in synaptic

density.Early cognitive development is accompanied

by a marked increase in synapse density in different

regions of the human cerebral cortex. Developmen-

tal landmarks through age 10 months are indicated.

The density of cortical synapses declines with age.

(Adapted from Huttenlocher 2002.)

These findings have two major implications for

understanding how aging affects the nervous system.

First, the biochemical mechanisms that lead to, or pro-

tect us from, the ravages of age are likely contribu-

tors to the changes in neurons that lead to age-related

cognitive decline. Research to explore this link

between cellular change and cognitive functioning is

now underway in model organisms. Second, and per-

haps more exciting, research on the pathways uncov-

ered by genetic studies can identify pharmacological

年轻

年老

树突小棘神经肌肉突触

Birth Months

Stereoacuity,

stereopsis

Visual

acuity

Smooth

pursuit

Thousands of synapses per neuron

Years

246810 12 25 10 20

30 50

Kandel-Ch64_1561-1582.indd 1565 19/01/21 9:21 AM

图 64.1.3: 树突和突触结构与年龄相关的变化。啮齿动物的皮层锥体神经元随着年龄的增长而失去树突棘。啮齿

动物的神经肌肉突触也表现出与年龄相关的结构变化。

Chapter 64 / The Aging Brain 1565

Figure 64–4 Age-related changes in dendritic and

synaptic structure.Cortical pyramidal neurons in

rodents lose dendritic spines with age. Neuromuscular

synapses in rodents also exhibit age-related changes in

structure. (Spine images reproduced, with permission,

from J. Luebke; synapse images reproduced, with per-

mission, from G. Valdez.)

Figure 64–5 Age-related changes in synaptic

density.Early cognitive development is accompanied

by a marked increase in synapse density in different

regions of the human cerebral cortex. Developmen-

tal landmarks through age 10 months are indicated.

The density of cortical synapses declines with age.

(Adapted from Huttenlocher 2002.)

These findings have two major implications for

understanding how aging affects the nervous system.

First, the biochemical mechanisms that lead to, or pro-

tect us from, the ravages of age are likely contribu-

tors to the changes in neurons that lead to age-related

cognitive decline. Research to explore this link

between cellular change and cognitive functioning is

now underway in model organisms. Second, and per-

haps more exciting, research on the pathways uncov-

ered by genetic studies can identify pharmacological

Young

Aged

Dendritic spines Neuromuscular synapse

出生月

立

体视锐度、

立体视觉

视觉

敏锐度

平滑

跟踪

每个神经元有数千个突触

年

246810 12 25 10 20

30 50

Kandel-Ch64_1561-1582.indd 1565 19/01/21 9:21 AM

图 64.1.4: 突触密度与年龄相关的变化。早期认知发展伴随着人类大脑皮层不同区域突触密度的显著增加。显示

了 10 个月大的发育标志。皮层突触的密度随着年龄的增长而下降

[559]

。

1381

64.2 相当一部分老年人的认知能力下降是显著的并且使人虚弱

1566

% 存活

老鼠

天

蠕虫

% 存活

野生型

100

100120

100

苍蝇

% 存活

野生型

Methuselah

（G蛋白偶联受体）

020406

Ames 侏儒症

（生长激素受体信号传导）

野生型

5000700 900 1,100 1,300 1,500

脂质代谢

胰岛素

样

受体

图 64.1.5: 寿命可以通过基因突变来增加。特定受体和信号蛋白的基因突变显著延长了蠕虫、苍蝇和小鼠突变株

的寿命，表明遗传调节机制影响衰老和寿命

[560-562]

。

1382

64.3 阿尔茨海默病是痴呆症最常见的原因

标志物可以提示潜在的阿尔茨海默病病理学的存在。然而，到目前为止，还没有很好的生物标志物来预测由阿

尔茨海默病以外的疾病引起的轻度认知损伤患者发展为痴呆症。

Chapter 64 / The Aging Brain 1567

Figure 64–7 Cognitive performance can vary

widely with age.The chart shows current thinking

about the etiology of Alzheimer disease (AD). This

gradual process, which results from a combination

of biological, genetic, environmental, and lifestyle

factors, eventually sets some people on a course

to mild cognitive impairment (MCI) and then

dementia. Other people, with a different genetic

makeup or a different combination of factors over

a lifetime, continue on a course of healthy cogni-

tive aging. (From the National Institute on Aging:

http://www.nia.nih.gov/alzheimers/publication/

part-2-what-happens-brain-ad/changing-brain-ad.)

Like MCI, dementia is also a syndrome that

involves progressive impairment of memory as well

as other cognitive abilities such as language, problem

solving, judgment, calculation, or attention. It is asso-

ciated with a variety of diseases. The most common

is Alzheimer disease, as discussed below. The second

most common cause in the elderly is cerebrovascular

disease, particularly strokes that lead to focal ischemia

and consequent infarction in the brain.

Large lesions in the cortex are often associated

with language disturbances (aphasia), hemiparesis, or

neglect syndromes, depending on which portions of

the brain are compromised. Small infarctions in white

matter or deeper structures of the brain, termed

lacunes, also occur as a consequence of hypertension

and diabetes. In small numbers, these infarctions may

be asymptomatic, or they may contribute to what

appears to be normal age-associated cognitive decline or

certain cases of MCI. As vascular lesions increase in

number and size, however, their effects accumulate,

and eventually, they can lead to dementia.

Numerous other conditions can lead to dementia,

including Parkinson disease, Lewy body dementia,

frontotemporal dementia, alcoholism, drug intoxica-

tions, infections such as HIV and syphilis, brain tumors,

subdural hematomas, repeated brain trauma, vitamin

deficiencies (notably lack of vitamin B

), thyroid

disease, and a variety of other metabolic disorders.

Repeated brain trauma can result in what is termed

chronic traumatic encephalopathy (CTE). Numerous

cases of CTE in American professional athletes have

recently been reported. In some patients, schizophre-

nia or depression may mimic a dementia syndrome.

(Emil Kraepelin chose the term “dementia praecox” to

describe the cognitive disease that we now call schizo-

phrenia.) Because some dementias can be treated, it is

important for the physician to probe differential diag-

noses of dementia based on clinical history, physical

examinations, and laboratory studies.

Alzheimer Disease Is the Most Common

Cause of Dementia

In 1901, Alois Alzheimer examined a middle-aged

woman who had developed a progressive loss of cog-

nitive abilities. Her memory became increasingly

impaired. She could no longer orient herself, even in

her own home, and she hid objects in her apartment. At

times, she believed that people intended to murder her.

She was institutionalized in a psychiatric hospital

and died approximately 5 years after she was first seen

by Dr. Alzheimer. After death, Alzheimer performed

an autopsy that revealed specific alterations in the

cerebral cortex, described below. The constellation of

behavioral symptoms and physical alterations was

subsequently given the name Alzheimer disease (AD).

This case caught Alzheimer’s attention because it

occurred in middle age; the initial clinical manifesta-

tions of AD (usually memory loss and decreased execu-

tive function) most commonly appear after age 65. The

prevalence of AD at age 70 is about 2%, whereas after

age 80, it is greater than 20%. Early-onset cases before

age 65 are often familial (autosomal dominant AD), and

gene mutations have been discovered in many of these

patients, as we shall discuss below. In fact, new genetic

tests on preserved brain samples from Alzheimer’s

first case recently showed that her disease resulted

认知水平

40 60 80

年龄

正常年龄

相关记忆丧失

独立功能

完全丧失

遗忘型轻度认知障碍：

记忆问题；

其他认知功能还可以；

大脑补偿变化

阿尔兹海默的大脑变

化在症状出现前几十

年就开始了

健康老化

阿尔兹海默临床前期

遗忘型轻度认知障碍

临床诊断的阿尔兹海默

阿尔兹海默

患者认知

能力下降加速

Kandel-Ch64_1561-1582.indd 1567 19/01/21 9:21 AM

图 64.2.1: 认知能力随年龄变化很大。该图表显示了当前对阿尔茨海默病病因的思考。这个渐进的过程是由生物、

遗传、环境和生活方式因素共同作用的结果，最终使一些人走上轻度认知损伤的道路，然后是痴呆症。而其他具

有不同遗传构成或一生中不同因素组合的人则继续保持健康的认知老化过程（来自国家老龄化研究所）。

与轻度认知损伤一样，痴呆症也是一种涉及记忆力以及其他认知能力（如语言、问题解决、判断、计算或注

意力）进行性损害的综合症。它与多种疾病有关。最常见的是阿尔茨海默病，如下所述。老年人中第二个最常见

的原因是脑血管疾病，特别是导致局灶性缺血和随之而来的脑梗塞的中风。

皮层中的大损伤通常与语言障碍（失语症）、偏瘫或忽视综合症有关，具体取决于大脑的哪些部分受到损害。

高血压和糖尿病也会导致白质或大脑深层结构中出现小梗塞，称为腔隙性梗塞。在少数情况下，这些梗塞可能

没有症状，或者它们可能导致看似正常的与年龄相关的认知能力下降或某些轻度认知损伤病例。然而，随着血

管病变数量和大小的增加，它们的影响会累积，最终会导致痴呆。

许多其他情况可导致痴呆，包括帕金森病、路易体痴呆、额颞痴呆、酒精中毒、药物中毒、艾滋病毒和梅毒

等感染、脑肿瘤、硬膜下血肿、反复脑外伤、维生素缺乏症（尤其是缺乏维生素 B12）、甲状腺疾病和各种其他

代谢紊乱。反复的脑外伤会导致所谓的慢性创伤性脑病。最近报道了许多美国职业运动员的慢性创伤性脑病病

例。在一些患者中，精神分裂症或抑郁症可能类似于痴呆症。埃米尔 · 克雷佩林选择术语“早发性痴呆”来描述

我们现在称为精神分裂症的认知疾病）。因为一些痴呆症是可以治疗的，所以医生根据临床病史、体检和实验室

研究来探索痴呆症的鉴别诊断是很重要的。

64.3 阿尔茨海默病是痴呆症最常见的原因

1901 年，阿尔茨海默检查了一名中年妇女，她出现了认知能力逐渐丧失的情况。她的记忆力越来越差。她

甚至在自己的家中也无法辨别方向，她也把东西藏在了自己的公寓里。有时，她认为人们打算谋杀她。

她被送进了一家精神病院，并在阿尔茨海默博士第一次见到她大约 5 年后去世。死后，阿尔茨海默进行了

尸检，发现了大脑皮层的特定改变，如下所述。一系列行为症状和身体改变随后被命名为阿尔茨海默病。

1383

64.4 阿尔茨海默病患者的大脑因萎缩、淀粉样斑块和神经原纤维缠结而改变

这个病例引起了阿尔茨海默的注意，因为它发生在中年；阿尔茨海默病的最初临床表现（通常是记忆力减

退和执行功能下降）最常出现在 65 岁以后。70 岁时阿尔茨海默病的患病率约为 2%，而 80 岁后则超过 20%。65

岁之前的早发病例通常是家族性的（常染色体显性遗传性阿尔茨海默病），并且已经在其中许多患者中发现了基

因突变，我们将在下面讨论。事实上，最近对第一例阿尔茨海默病患者保存的大脑样本进行的新基因测试表明，

她的疾病是由一种叫做早老素-1 的基因突变引起的，这是家族性或显性遗传性阿尔茨海默病的最常见原因。迟

发性阿尔茨海默病（65 岁或以上发病）通常是散发性的，这意味着不存在显性遗传性阿尔茨海默病中出现的单

一致病基因。尽管如此，很明显，遗传学甚至更可能通过影响易感性的变异，以及刚刚被发现的环境和其他促成

因素，对晚发性阿尔茨海默病的风险做出巨大贡献。

阿尔茨海默病的早发型和晚发型类型通常都表现出情景记忆和执行功能的选择性缺陷。起初，语言、力量、

反应、感觉能力和运动技能几乎正常。然而，记忆和注意力会逐渐丧失，连同解决问题、语言、计算和视觉空间

感知等认知能力也会丧失。不出所料，这些认知丧失会导致行为改变，一些患者会出现幻觉和妄想等精神病症

状。所有患者均出现精神功能和日常生活活动进行性损害；在晚期阶段，他们变得哑巴、大小便失禁和卧床不

起。

阿尔茨海默病影响大约 1/8 的 65 岁以上老年人。现在美国有超过 500 万人因阿尔茨海默病而患上痴呆症。

由于老年人口快速增加，阿尔茨海默病风险人群也在快速增长。在接下来的 25 年里，美国患有阿尔茨海默病的

人数预计将增加 2 倍，照顾无法自理的患者的费用也将增加 3 倍。因此，阿尔茨海默病是社会的一个主要公共

健康问题。

64.4 阿尔茨海默病患者的大脑因萎缩、淀粉样斑块和神经原纤维缠结而改变

在阿尔茨海默病中发现了 3 类大脑异常。首先，如图 64.4.1 所示，由于神经元和突触丢失，大脑萎缩，脑回

变窄，脑沟变宽，脑重量减轻，脑室扩大。这些变化也以较轻微的形式出现在因其他原因死亡的认知完好老年人

身上。因此，阿尔茨海默病是一种神经退行性疾病。

其次，阿尔茨海默病患者的大脑含有主要由聚集形式的称为淀粉样蛋白-β 或 Aβ 的肽组成的细胞外斑块，它

是从正常产生的蛋白质中切割下来的。如图 64.4.2 所示，Aβ 的聚集体称为淀粉样斑块。斑块中的大部分 Aβ 是

纤维状的；Aβ 的聚集体与其他与 Aβ 共聚集的蛋白质一起出现在 β 折叠片构象中。当用刚果红等染料染色时，

淀粉样蛋白可以被检测到，当在偏振光下观察时，或者当用硫黄素 S 染色并用荧光光学器件观察时，淀粉样蛋

白是折射的。淀粉样蛋白的细胞外沉积物被肿胀的轴突和树突包围（神经炎性营养不良）。这些神经元过程又被

激活的星形胶质细胞和小胶质细胞（炎症细胞）的细胞过程所包围。Aβ 还可以在大脑小动脉壁形成淀粉样沉积

物，产生所谓的脑淀粉样血管病。这在高达 90% 的阿尔茨海默病患者中不同程度地发生，但它也可以独立于阿

尔茨海默病发生。脑淀粉样血管病可导致缺血性中风，是老年人出血性中风的常见原因。

第三，如图 64.4.2 所示，许多受到阿尔茨海默病病理学影响但仍然存活的神经元具有细胞骨架异常，其中最

显著的是神经原纤维缠结和神经纤维丝的积累。缠结是细胞体和树突中的丝状内含物，包含成对的螺旋丝和 15

纳米直丝。这些细丝由正常微管相关蛋白 tau 的聚集形式组成。

在阿尔茨海默病中，缠结不是均匀分布于整个大脑，而是会影响特定区域。如图 64.4.3 所示，内嗅皮层、海

马体、部分新皮层和基底核特别脆弱。内嗅皮层和海马体的改变可能是情景记忆问题的基础，而情景记忆是阿

尔茨海默病的首发症状之一。基底前脑胆碱能系统的异常可能导致认知困难和注意力缺陷。这些胆碱能异常与

额纹状体回路中的异常形成对比，后者与正常受试者的年龄相关认知能力下降相关。解剖差异、病理变化、广泛

的神经元死亡和基因突变（见下文）的结合反对曾经流行的观点，即阿尔茨海默病是正常衰老过程的异常形式。

64.4.1 淀粉样斑块含有有助于阿尔茨海默病病理学的有毒肽

淀粉样斑块的主要成分，即 Aβ 肽的聚集体，基于其低溶解度，于 1980 年代初首次通过离心分离。主要肽

的长度为 40 和 42 个氨基酸（40 个残基加上羧基末端的 2 个额外氨基酸）。生化研究表明，Aβ42 肽比 Aβ40 更

快地成核成淀粉样原纤维。

1384

64.4 阿尔茨海默病患者的大脑因萎缩、淀粉样斑块和神经原纤维缠结而改变

1568 Part IX / Diseases of the Nervous System

Figure 64–8 Overt pathological changes in the brain of

individuals with Alzheimer disease.When compared to age-

matched normal brains, the brain of an Alzheimer patient dis-

plays marked shrinkage and ventricular enlargement. (See also

Figure 64–3.) (Whole brain photos reproduced, with permis-

sion, from University of Alabama at Birmingham Department

of Pathology © PEIR Digital Library [http://peir.net]; brain slice

photos reproduced, with permission, from A.C. McKee.)

from a mutation of a gene called presenilin-1, the

most common cause of familial or dominantly inher-

ited AD. Late-onset AD (onset at age 65 or greater) is

more often sporadic, implying that there is no single

causative gene as occurs in dominantly inherited AD.

Nonetheless, it is clear that genetics contribute greatly

to risk for even late-onset AD more likely through

variants that affect susceptibility, along with environ-

mental and other contributing factors that are just now

being uncovered.

Both early-onset and late-onset varieties of AD usu-

ally present with a selective defect in episodic memory

and executive function. At first, language, strength,

reflexes, and sensory abilities and motor skills are nearly

normal. Gradually, however, memory and attention are

lost, along with cognitive abilities such as problem solv-

ing, language, calculation, and visuospatial perception.

Unsurprisingly, these cognitive losses lead to behavioral

alterations, and some patients develop psychotic symp-

toms such as hallucinations and delusions. All patients

suffer progressive impairment of mental functions and

activities of daily living; in the late stages, they become

mute, incontinent, and bedridden.

Alzheimer disease affects approximately one-eighth

of people older than 65 years. More than 5 million

people in the United States now suffer from dementia

due to AD. Because the elderly population is increas-

ing rapidly, the population at risk for AD is growing

rapidly. During the next 25 years, the number of peo-

ple with AD in the United States is expected to triple,

as will the cost of caring for patients no longer able to

care for themselves. Thus, AD is one of society’s major

public health problems.

The Brain in Alzheimer Disease Is Altered

by Atrophy, Amyloid Plaques, and

Neurofibrillary Tangles

Three categories of brain abnormalities are found in

AD. First, because of neuronal and synaptic loss, the

brain is atrophied, with narrowed gyri, widened sulci,

reduced brain weight, and enlarged ventricles (Figure

64–8). These changes are also seen in milder forms in

cognitively intact elderly people who die from other

causes. Thus, AD is a neurodegenerative disease.

正常

阿尔茨海默病

Kandel-Ch64_1561-1582.indd 1568 19/01/21 9:22 AM

图 64.4.1: 阿尔茨海默病患者大脑的明显病理变化。与年龄匹配的正常大脑相比，阿尔茨海默病患者的大脑显示

出明显的萎缩和脑室扩大（另请参见图 64.1.2）。

Chapter 64 / The Aging Brain 1569

Figure 64–9 Plaques and tangles in the Alzheimer brain.A

section of cerebral cortex from the brain of an individual with

severe Alzheimer disease shows characteristic plaques and

neurofibrillary tangles. (Images reproduced, with permission,

from James Goldman.)

Left:The diagram shows a neuron containing neurofibrillary

tangles in the cell body and axon. Amyloid plaques are shown

in the neuropil; one of them surrounds a dendrite, which dis-

plays an altered, swollen shape. Tangles, composed of bundles

of paired helical filaments, are comprised of abnormal poly-

mers of hyperphosphorylated tau protein, and amyloid plaques

are extracellular deposits of polymers of the amyloid-β (A4)

peptide.

Middle:A section of neocortex from a patient with Alzheimer

disease treated with a silver stain shows neuronal cell bodies

containing neurofibrillary tangles and neuropil containing amy-

loid plaques.

Right:A higher magnification of the cortex shows neurofibril-

lary tangles in neuronal cell bodies and a healthy neuron with-

out a tangle. Many thin silver-positive cell processes are seen in

the neuropil.

Second, the brains of AD patients contain extracel-

lular plaques composed predominantly of an aggre-

gated form of a peptide called amyloid-β, or Aβ, which

is cleaved from a normally produced protein. Aggre-

gates of Aβ are called amyloid plaques. Much of the

Aβ in plaques is fibrillar; aggregates of Aβ appear in

a β-pleated sheet conformation along with other pro-

teins that co-aggregate with Aβ (Figure 64–9). Amyloid

can be detected when stained with dyes such as Congo

red, and is refractive when viewed in polarized light

or when stained with thioflavin S and viewed with

fluorescence optics. The extracellular deposits of amy-

loid are surrounded by swollen axons and dendrites

(neuritic dystrophy). These neuronal processes in turn

are surrounded by the cell processes of activated astro-

cytes and microglia (inflammatory cells). Aβ can also

form amyloid deposits in the walls of arterioles in the

brain, producing what is known as cerebral amyloid

angiopathy. This occurs to varying extents in up to 90%

of patients who develop AD, but it can also occur inde-

pendently of AD. Cerebral amyloid angiopathy can

lead to ischemic stroke, and it is a common cause of

hemorrhagic stroke in the elderly.

Third, many neurons that are affected by Alzheimer

pathology but still alive have cytoskeletal abnormali-

ties, the most dramatic of which is the accumulation

of neurofibrillary tangles and neuropil threads (Figure

64–9). The tangles are filamentous inclusions in the cell

bodies and dendrites that contain paired helical fila-

ments and 15-nm straight filaments. These filaments

are made up of an aggregated form of the normal

microtubule-associated protein tau.

In AD, tangles do not occur uniformly through-

out the brain, but rather affect specific regions. The

entorhinal cortex, the hippocampus, parts of the neo-

cortex, and the nucleus basalis are especially vulner-

able (Figure 64–10). Alterations in the entorhinal cortex

and hippocampus likely underlie the problems with

episodic memory that are among the first symptoms

of AD. Abnormalities in the basal forebrain cholinergic

systems may contribute to cognitive difficulties and

attention deficits. These cholinergic abnormalities con-

trast with those in frontostriatal circuits that correlate

with age-related cognitive decline in normal subjects.

The combination of anatomical differences, pathologi-

cal changes, widespread neuronal death, and genetic

斑块

缠结

不规则的

树突

双螺旋丝

缠结

健康

神经元

Kandel-Ch64_1561-1582.indd 1569 19/01/21 9:22 AM

图 64.4.2: 阿尔茨海默病大脑中的斑块和缠结。患有严重阿尔茨海默病的人的大脑皮层部分显示出特征性斑块和

神经原纤维缠结。左图：该图显示了 1 个神经元，其细胞体和轴突中含有神经原纤维缠结。淀粉样斑块显示在神

经细胞中；其中一个围绕着一个树突，树突显示出一种改变的、肿胀的形状。缠结由成对的螺旋丝束组成，由过

度磷酸化的 tau 蛋白的异常聚合物组成，而淀粉样斑块是淀粉样蛋白-β（A4）肽聚合物的细胞外沉积物。中图：

阿尔茨海默病患者的新皮层部分经银染处理后显示含有神经原纤维缠结的神经元细胞体和含有淀粉样蛋白斑块

的神经细胞。右：皮层的更高放大倍数显示神经元细胞体中的神经原纤维缠结和没有缠结的健康神经元。在神

经胶质细胞中可以看到许多薄的银阳性细胞突起。

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64.4 阿尔茨海默病患者的大脑因萎缩、淀粉样斑块和神经原纤维缠结而改变

1570 Part IX / Diseases of the Nervous System

Figure 64–10 Neurofibrillary

tangles and senile plaques are

concentrated in different regions

of the Alzheimer brain. (Adapted,

with permission, from Arnold et al.

University Press.)

mutations (see below) argue against the idea, once

prevalent, that AD is an aberrant form of normal aging

processes.

Amyloid Plaques Contain Toxic Peptides That

Contribute to Alzheimer Pathology

The main constituent of amyloid plaques, aggregates

of Aβ peptides, were first isolated in the early 1980s

by centrifugation, based on their low solubility. The

predominant peptides were 40 and 42 amino acids

in length (the 40 residues plus two additional amino

acids at the carboxy terminal end). Biochemical studies

showed that the Aβ42 peptide nucleates more rapidly

than Aβ40 into amyloid fibrils.

Considerable experimental evidence indicates that

Aβ42 drives the initial aggregation, although Aβ40

also accumulates to a significant extent, especially in

cerebral amyloid angiopathy. For neurons in culture,

the forms of the Aβ42 peptide that are larger than a

monomer are generally more toxic than aggregated

forms of Aβ40. These results implicate Aβ42 as a key

driver of amyloid formation as well as Aβ toxicity.

Once it was discovered that Aβ peptides 38 to

43 amino acids in length are formed by cleavage of

a precursor protein, researchers set out to isolate the

precursor. The precursor was found in the mid-1980s,

molecularly cloned, and named the amyloid precursor

protein (APP). It is a large transmembrane glycoprotein

that is present in all types of cells but is expressed at its

highest levels in neurons. The normal functions of APP

in the brain are not understood.

How is APP processed to form Aβ peptides? The

answer has turned out to be complex. Three enzymes,

α-, β-, and γ-secretase, cut APP into pieces. The β- and

γ-secretases cleave APP to generate soluble extracel-

lular fragments that are released into the interstitial

fluid. These are the Aβ peptides, which include part

of the transmembrane segment of APP (Figure 64–11).

The cleavage by γ-secretase is unusual in that it occurs

in a membrane-spanning portion of APP, a region long

thought to be immune from hydrolysis because it is

surrounded by lipids rather than water. Cleavage by

α-secretase in the middle of the Aβ sequence prevents

the formation of Aβ peptides.

The enzymes that account for α-, β-, and

γ-secretases have been isolated and characterized.

The enzyme α-secretase is a member of a large fam-

ily of extracellular proteases called ADAM (a disin-

tegrin and metalloproteinase) that are responsible

最小密度

最大密度

神经原纤维缠结

老年斑

Kandel-Ch64_1561-1582.indd 1570 19/01/21 9:22 AM

图 64.4.3: 神经原纤维缠结和老年斑集中在阿尔茨海默病大脑的不同区域

[563]

。

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64.4 阿尔茨海默病患者的大脑因萎缩、淀粉样斑块和神经原纤维缠结而改变

相当多的实验证据表明，Aβ42 驱动初始聚集，尽管 Aβ40 也在显著程度上积累，尤其是在脑淀粉样血管病

中。对于培养的神经元，比单体大的 Aβ42 肽形式通常比 Aβ40 的聚集形式毒性更大。这些结果暗示 Aβ42 是淀

粉样蛋白形成和 Aβ 毒性的关键驱动因素。

一旦发现长度为 38 至 43 个氨基酸的 Aβ 肽是由前体蛋白的裂解形成的，研究人员便着手分离前体。该前体

于 20 世纪 80 年代中期被发现，经过分子克隆，并命名为淀粉样前体蛋白。它是一种大型跨膜糖蛋白，存在于所

有类型的细胞中，但在神经元中表达水平最高。淀粉样前体蛋白在大脑中的正常功能尚不清楚。

淀粉样前体蛋白是如何加工形成 Aβ 肽的？结果证明答案很复杂。α-、β-和 γ-分泌酶这 3 种酶将淀粉样前

体蛋白切成碎片。β- 和 γ- 分泌酶裂解淀粉样前体蛋白产生可溶性细胞外片段，释放到间质液中。如图 64.4.4 所

示，这些是 Aβ 肽，包括淀粉样前体蛋白的跨膜部分。γ-分泌酶的切割是不寻常的，因为它发生在淀粉样前体蛋

白的跨膜部分，该区域长期以来被认为不受水解影响，因为它被脂质而不是水包围。在 Aβ 序列中间被 α-分泌

酶切割可防止 Aβ 肽的形成。

已经分离和表征了负责 α-、β- 和 γ- 分泌酶的酶。α-分泌酶是称为一种去整合蛋白和金属蛋白酶的细胞外蛋

白酶大家族的成员，负责降解细胞外基质的许多成分。β-分泌酶，称为 BACE1（β-位点淀粉样前体蛋白裂解酶

1），是中枢神经元中的一种跨膜蛋白，集中在突触中。来自缺乏 BACE1 的突变小鼠的脑细胞不产生 Aβ 肽，证

明 BACE1 确实是神经元 β-分泌酶。γ-分泌酶是三者中最复杂的，实际上是一种多蛋白复合物，可以切割几种不

同的跨膜蛋白。正如预期的那样，鉴于其在膜内发挥作用的特殊能力，γ-分泌酶本身包括几种跨膜蛋白。其中 2

个称为早老素 1 和早老素 2，反映了它们与阿尔茨海默病的关联。该复合物的其他成分包括跨膜蛋白 nicastrin、

Aph-1 和 Pen-2。

尽管 Aβ 和淀粉样前体蛋白的生化特性很有趣，但关键问题是它们是否参与了阿尔茨海默病的衰弱症状。该

疾病可能是由 Aβ 积累引起的，但 Aβ 本身可能是另一种病理过程的结果，甚至是无害的相关因素。人类和实验

动物的遗传证据对于证明淀粉样前体蛋白，特别是 Aβ 在阿尔茨海默病中发挥核心作用至关重要。

第一条线索来自对淀粉样前体蛋白基因位于 21 号染色体上的观察，唐氏综合症患者（也称为 21 三体综合

症）中存在 3 个拷贝，而不是正常的 2 个拷贝。所有活到中年的唐氏综合症患者都会在 50 岁左右出现阿尔茨海

默病病理和痴呆症。这种关联与淀粉样前体蛋白通过在整个生命过程中过量产生淀粉样前体蛋白和 Aβ 50% 来

诱发阿尔茨海默病的观点是一致的。然而，许多基因的拷贝在 21 三体个体中以 3 个拷贝存在，最初，尚不清楚

唐氏综合症中淀粉样前体蛋白的 3 倍体是导致该人群阿尔茨海默病的原因。随后，由于人类 21 号染色体上淀粉

样前体蛋白基因座的重复，发现了在没有唐氏综合症的情况下同时发生阿尔茨海默病和脑淀粉样血管病的罕见

家族。这是强有力的证据表明，仅淀粉样前体蛋白的过度表达就足以导致阿尔茨海默病和脑淀粉样血管病。

更直接的遗传证据来自对罕见的显性遗传性阿尔茨海默病患者的分析，这些患者的症状发作通常在 30 至 50

岁之间。在 20 世纪 80 年代后期，几个研究小组开始使用分子克隆方法来鉴定在显性遗传阿尔茨海默病中发生

突变的基因。值得注意的是，如图 64.4.5 所示，识别出的前 3 个基因是编码蛋白质淀粉样前体蛋白、presenilin-1

和 presenilin-2 的基因。在这 3 个基因中发现了许多不同的突变，大多数影响淀粉样前体蛋白的切割，增加 Aβ

肽的产生，或者特别是更容易聚集的 Aβ42 物种的比例。有趣的是，一些淀粉样前体蛋白突变发生在 Aβ 序列本

身内，不会影响 Aβ 的产生，但会影响 Aβ 的聚集和从大脑中清除。

一些淀粉样前体蛋白突变是 Aβ 区域两侧的氨基酸置换。在 β-分泌酶切割位点表达双重突变的细胞（所谓

的瑞典突变）是 Aβ 形成所必需的，其分泌的 Aβ 肽比表达野生型淀粉样前体蛋白的细胞多几倍。有趣的是，最

近发现了与 β-分泌酶位点相邻的淀粉样前体蛋白中的另一个突变。这种突变似乎通过减少 Aβ 的产生来预防阿

尔茨海默病。另一个淀粉样前体蛋白突变导致 γ-分泌酶产生更大比例的较长 Aβ 种类（例如 Aβ42）相对于较短

的种类（例如 Aβ40）。同样，在大多数早老素突变体中，突变体 γ-分泌酶的活性高于正常水平或产生 Aβ42 与

Aβ40 比例增加的肽。

这些人类遗传学研究提供了令人信服的证据，证明（1）淀粉样前体蛋白裂解产生 Aβ 和 Aβ 聚集的倾向在

某些显性遗传的早发性阿尔茨海默病病例中起着关键的促进作用，以及（2）较少的 Aβ 产生降低了晚发的风险。

小鼠遗传学研究也加强了淀粉样前体蛋白切割，特别是 Aβ 聚集导致阿尔茨海默病的情况。转基因表达或敲入与

常染色体显性遗传阿尔茨海默病中发现的相同的突变淀粉样前体蛋白形式导致海马和皮层中出现淀粉样蛋白斑

块、Aβ 沉积物附近的营养不良神经突、淀粉样蛋白斑块周围突触末稍密度降低和损伤，以及突触传递受损。一

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64.4 阿尔茨海默病患者的大脑因萎缩、淀粉样斑块和神经原纤维缠结而改变

Chapter 64 / The Aging Brain 1571

Figure 64–11 Processing of the amyloid precursor protein,

generation of the Aβ peptide, and downstream effects on

tau aggregation.The Aβ peptide is produced from the amyloid

precursor protein (APP), a transmembrane protein, via cleav-

age by two enzymes, β-secretase and γ-secretase. (Cleavage

by α-secretase prevents Aβ production.) Presenilin is the active

enzymatic component of the γ-secretase complex and cleaves

APP at several sites within the membrane to produce Aβ

peptides of different lengths such as Aβ38, Aβ40, and Aβ42.

Several mutations in APP that are just outside of the Aβ region

or within the coding sequence of Aβ cause forms of autoso-

mal dominant Alzheimer disease (AD). The amino acids (blue)

in the APP/Aβ amino acid sequence represent the normal

amino acids in APP; amino acids in green (below the normal

sequence) are those that cause familial AD or cerebral amyloid

angiopathy (CAA). Aβ is predominantly produced from APP

within endosomes. A variety of molecules and synaptic activity

regulate Aβ levels. There is evidence that Aβ aggregation is

influenced by the Aβ-binding molecules ApoE and clusterin,

which likely interact in the extracellular space of the brain. A

variety of molecules and processes affect Aβ clearance from

the interstitial fluid (ISF) that is present in the extracellular

space of the brain, including neprilysin and insulin-degrading

enzyme (IDE), as well as cerebral spinal fluid and interstitial

fluid bulk flow. LRP1 and RAGE (receptor for advanced glyca-

tion end products) appear to influence Aβ transport across the

blood–brain barrier. The concentration and type of Aβ influence

aggregation (Aβ42 is more fibrillogenic). Once it aggregates

into oligomers and fibrils, it can be directly toxic to cells, induce

inflammation, and exacerbate the conversion of soluble tau to

aggregated tau through mechanisms that remain unclear. In

addition to Aβ, a variety of factors influence tau aggregation

and toxicity, including tau levels, sequence, and phosphoryla-

tion state. (Abbreviation: AICD, APP intracellular domain.)

NL RN GQN

Aβ

聚集体

淀粉样

前体蛋白

可溶性

不溶性

tau

TEEISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK

1111

04249

毒性

家族性阿尔

茨海默病或

脑淀粉样血

管病变的

病因

AICD

Aβ38

Aβ40

Aβ42

（易于聚集）

β-分泌酶 α-分泌酶 γ-分泌酶

Aβ

-分泌酶

γ-分泌酶

(早老素组分)

LMVI

AATL

Kandel-Ch64_1561-1582.indd 1571 19/01/21 9:22 AM

图

64.4.4

: 淀粉样蛋白前体蛋白的加工、

肽的产生以及对

tau

聚集的下游影响。

肽是由

淀粉样前体蛋白

（一

种跨膜蛋白）通过 2 种酶（β-分泌酶和 γ-分泌酶）裂解产生的（α-分泌酶的切割可防止 Aβ 的产生）。早老素

是 γ-分泌酶复合物的活性酶促成分，可在膜内的多个位点切割淀粉样前体蛋白以产生不同长度的 Aβ 肽，例如

Aβ38、Aβ40 和 Aβ42。淀粉样前体蛋白中位于 Aβ 区域之外或 Aβ 编码序列内的几种突变会导致常染色体显性

阿尔茨海默病的形式。淀粉样前体蛋白/Aβ 氨基酸序列中的氨基酸（蓝色）代表淀粉样前体蛋白中的正常氨基

酸；绿色氨基酸（低于正常序列）是导致家族性阿尔茨海默病或脑淀粉样血管病变的氨基酸。Aβ 主要由核内体

内的

淀粉样前体蛋白

产生。多种分子和突触活动调节

水平。有证据表明

聚集受

结合分子

ApoE

和凝

聚素的影响，它们可能在大脑的细胞外空间相互作用。多种分子和过程影响 Aβ 从存在于大脑细胞外空间的间质

液中清除，包括脑啡肽酶和胰岛素降解酶，以及脑脊髓液和间质液体积流量。LRP1 和晚期糖基化终产物受体似

乎影响 Aβ 穿过血脑屏障的转运。Aβ 的浓度和类型会影响聚集（Aβ42 更易形成纤维）。一旦它聚集成低聚物和

原纤维，它就会对细胞产生直接毒性，诱发炎症，并通过尚不清楚的机制加剧可溶性 tau 向聚集 tau 的转化。除

Aβ 外，还有多种因素影响 tau 聚集和毒性，包括 tau 水平、序列和磷酸化状态。

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64.4 阿尔茨海默病患者的大脑因萎缩、淀粉样斑块和神经原纤维缠结而改变

Chapter 64 / The Aging Brain 1573

Figure 64–12 Environmental and genetic factors play a role

in Alzheimer disease.

A.Environmental and genetic factors. (Abbreviations: APOE,

apolipoprotein E; APP, amyloid precursor protein; PS1,

presenilin-1; PS2, presenilin-2.)

B.Specific genes involved in early-onset Alzheimer disease

(AD).

C.Presenilin-1 (a component of the gamma secretase enzyme

complex) is associated with the APP protein within the plasma

membrane.

cytoplasmic fragment. Although all three fragments

can have deleterious effects on neurons in experi-

mental animals, the Aβ peptides have received the

most attention, and evidence for their involvement is

strongest. There is evidence that different aggregated

forms of Aβ such as oligomers, protofibrils, and fibrils

can lead to synaptic and neuronal damage that might

contribute to AD.

Neurofibrillary Tangles Contain Microtubule-

Associated Proteins

Until around 2005, most research on the molecular and

cellular basis of AD focused on Aβ peptides and amy-

loid plaques, but tau aggregation in neurofibrillary

tangles appears to play a key role in the progression

of AD (Figure 64–9). Molecular analysis revealed that

these abnormal inclusions in cell bodies and proximal

dendrites contain aggregates of hyperphosphorylated

isoforms of tau, a microtubule-binding protein that

is normally soluble (Figure 64–13). The tau protein

plays a key role in intracellular transport, particularly

in axons, by binding to and stabilizing microtubules.

Impairments in axonal transport compromise synaptic

stability and trophic support. While the mechanism by

which aggregation and hyperphosphorylation of tau

lead to toxicity is still not understood, tau accumula-

tion is clearly associated with neuronal degeneration.

Although tangles are a defining feature of AD, it

was initially unclear what role tangles and hyperphos-

phorylated forms of tau play in the pathogenesis of

the disease. Whereas mutations of APP and preseni-

lin genes can lead to AD, no mutations of the tau gene

have been found in familial AD. Nevertheless, there is

now a great deal of evidence indicating that tau aggre-

gation is a key factor in the neurodegeneration that

occurs in AD.

First, filamentous deposits of hyperphosphoryl-

ated tau are seen in a variety of neurodegenerative

disorders, including AD, forms of frontotemporal

dementia, progressive supranuclear palsy, corticoba-

sal degeneration, and CTE. Second, mutations in the

tau gene have been found to underlie another form

of autosomal dominant neurodegenerative disease:

frontotemporal dementia with Parkinson disease type

17 (FTPD17). These patients develop tau aggregation

together with brain atrophy in specific brain regions in

the absence of Aβ deposition. Third, progressive symp-

toms of AD correlate much better with the number and

distribution of tangles than with the amyloid plaques

淀粉样

前体蛋白

（30 变异）

早老蛋

白-1

（168 变异）

早老蛋

白-2

（10变异）

Alzheimer

disease

毒素

病毒

朊病毒

头部创伤

环境 + 遗传 (载脂蛋白E, 其他) + 变老

非遗传遗传

淀粉样前体蛋白

（21号染色体）

唐氏综合症

（21号三染色体）

早老蛋白-1

（14号染色体）

其他基因 (?)

淀粉样前体蛋白

教育水平低

早老蛋白-1

(

γ-分泌酶)

早发性家族阿尔茨海默病 %

Kandel-Ch64_1561-1582.indd 1573 19/01/21 9:22 AM

早老蛋白-2

（1号染色体）

图 64.4.5: 环境和遗传因素在阿尔茨海默病中发挥作用。A. 环境因素和遗传因素。B. 早发性阿尔茨海默病中涉及

的特定基因。C. 早老蛋白-1（γ 分泌酶复合物的一种成分）与质膜内的淀粉样前体蛋白相关。

些小鼠模型出现比如空间记忆和情景记忆缺陷的功能异常。在表达改变形式的淀粉样前体蛋白和早老蛋白-1 的

转基因小鼠中，改变更为严重。重要的是要注意，尽管这些小鼠不会出现 tau 聚集或神经原纤维缠结，这些病变

被认为在阿尔茨海默病中的认知能力下降中很重要，但它们仍然是解决 Aβ 的机制作用和阿尔茨海默病发病机

制中相关病理学的宝贵模型，尤其是 Aβ 的作用，以及用于测试潜在疗法。

鉴于淀粉样前体蛋白裂解参与阿尔茨海默病发病机制的有力证据，下一个问题是：裂解产物的积累如何导

致症状并最终导致痴呆？存在 3 组切割产物：分泌的细胞外区域（胞外域）、Aβ 肽和细胞质片段。尽管所有这 3

个片段都可能对实验动物的神经元产生有害影响，但 Aβ 肽受到的关注最多，而且其参与的证据也是最有力的。

有证据表明，Aβ 的不同聚集形式（例如低聚物、原纤维和纤维丝）可导致突触和神经元损伤，从而可能导致阿

尔茨海默病。

64.4.2 神经原纤维缠结含有微管相关蛋白

如图 64.4.2 所示，直到 2005 年左右，大多数关于阿尔茨海默病分子和细胞基础的研究都集中在 Aβ 肽和淀

粉样斑块上，但神经原纤维缠结中的 tau 聚集似乎在阿尔茨海默病的进展中起着关键作用。如图 64.4.6 所示，分

子分析表明，细胞体和近端树突中的这些异常内含物含有过度磷酸化的 tau 异构体的聚集体，tau 是一种通常可

溶的微管结合蛋白。tau 蛋白通过结合并稳定微管，在细胞内运输中发挥关键作用，尤其是在轴突中。轴突运输

受损会损害突触稳定性和营养支持。虽然 tau 蛋白的聚集和过度磷酸化导致毒性的机制尚不清楚，但 tau 蛋白的

积累显然与神经元变性有关。

尽管缠结是阿尔茨海默病的一个决定性特征，但最初并不清楚缠结和过度磷酸化形式的 tau 在疾病的发病

机制中扮演什么角色。虽然淀粉样前体蛋白和早老素基因的突变可导致阿尔茨海默病，但在家族性阿尔茨海默

病中未发现 tau 基因的突变。然而，现在有大量证据表明 tau 聚集是阿尔茨海默病中发生的神经变性的关键因素。

首先，在多种神经退行性疾病中都可以看到过度磷酸化 tau 的丝状沉积物，包括阿尔茨海默病、各种形式的

额颞痴呆、进行性核上性麻痹、皮层基底节变性和慢性创伤性脑病。其次，已发现 tau 基因突变是另一种常染色

体显性神经退行性疾病形式的基础：额颞叶痴呆伴帕金森病 17 型。在没有 Aβ 沉积的情况下，这些患者在特定

1389

64.4 阿尔茨海默病患者的大脑因萎缩、淀粉样斑块和神经原纤维缠结而改变

B 阿尔茨海默病神经元

A 健康神经元

微管

微管缺陷

成对

螺旋丝

微管

Tau 蛋白

具有过量磷酸基团

的异常tau

神经原纤维

缠结

图 64.4.6: 神经原纤维缠结的形成。A. 在健康的神经元中，tau 蛋白与正常的微管结合但不是成对的螺旋丝，并

有助于神经元的结构完整性。B. 在患病的神经元中，tau 蛋白变得过度磷酸化并失去与开始分解的正常微管的联

系。然后它形成成对的螺旋丝，被隔离在神经原纤维缠结中。

1390

64.4 阿尔茨海默病患者的大脑因萎缩、淀粉样斑块和神经原纤维缠结而改变

脑区发生 tau 聚集和脑萎缩。第三，阿尔茨海默病的进行性症状与缠结的数量和分布的相关性要好于与尸检中观

察到的淀粉样蛋白斑块的相关性。例如，如图 64.4.7 所示，在该区域出现斑块之前，缠结通常首先在内嗅皮层和

海马体（早期记忆障碍的可能部位）的神经元中出现。

Chapter 64 / The Aging Brain 1577

Figure 64–16 Relationship of biomarker changes to cogni-

tive and clinical changes in Alzheimer disease (AD).In cogni-

tively normal people who are going to develop AD dementia, one

of the first physical signs is the initiation of Aβ aggregation in the

brain in the form of amyloid plaques. While people are still cogni-

tively normal, amyloid plaques continue to accumulate. At some

point, about 5 years before any clear-cut cognitive decline, tau

accumulation begins to increase in the neocortex, inflammation

and oxidative stress increase, and brain network connections

and metabolism begin to decline. Neuronal and synaptic loss and

brain atrophy also begin. This period—when the patient remains

cognitively normal but AD-type pathology is building up—is

termed preclinical AD. Once there is enough neuronal and synap-

tic dysfunction as well as cell loss, very mild dementia and mild

cognitive impairment become detectable. At that time, amyloid

deposition has almost reached its peak. As dementia worsens to

mild, moderate, and severe stages, neurofibrillary tangles form,

and neuronal and synaptic dysfunction, inflammation, cell death,

and brain atrophy worsen. (Adapted, with permission, from

Perrin, Fagan, and Holtzman 2009.)

have a treatment that delays the onset or slows the

progression of AD, there is hope that we are not too far

off from being able to mitigate symptoms. Although

there is no definitive proof, there is good evidence that

a variety of lifestyle factors decrease risk for AD. These

include high levels of education, cognitive stimulation,

staying socially engaged, regular exercise, not being

overweight, and getting appropriate amounts of sleep.

Present-day therapies focus on treating associated

symptoms such as depression, agitation, sleep disor-

ders, hallucinations, and delusions.

One of the principal therapeutic targets to date

has been the cholinergic system in the basal forebrain,

a region of the brain that is damaged in AD and that

contributes to attention. Acetylcholinesterase inhibi-

tors increase levels of acetylcholine by inhibiting its

breakdown and represent one of the few drug classes

approved by the FDA for treatment of AD. Another

drug, the N-methyl--aspartate (NMDA) receptor

antagonist memantine, also improves symptoms in

individuals with mild to moderate dementia due to

AD. It is believed that memantine’s action modulates

glutamate-mediated neurotransmission. Nevertheless,

these drugs exert only a modest effect on cognitive

functions and the activities of daily living.

Recent advances in our understanding of the

cell-biological basis of AD have produced several

promising new therapeutic targets, all of which are

being explored intensively. One approach is to develop

drugs that reduce or modulate the activity of the β- and

γ-secretases that cleave APP to generate Aβ peptides

and the associated soluble extracellular and intracellu-

lar fragments. In fact, decreasing either β- or γ-secretase

levels in transgenic mice that overexpress mutant APP

decreases Aβ deposition and, in some cases, functional

abnormalities.

Accordingly, pharmaceutical companies have

developed drugs that decrease or modulate levels

of β- and γ-secretases in humans. An obstacle to this

approach is that the secretases also act on substrates

other than APP, so decreasing their levels can have

deleterious side effects. This is especially true for

γ-secretase, whose inhibition has led to toxicity in

human trials for AD. There are now several β-secretase

inhibitors in clinical trials for AD, and it is likely such

drugs will also move into trials for what is called pre-

clinical AD, when AD pathology is accumulating but

there is no sign yet of cognitive decline (Figure 64–16).

The goal of this therapy would be to delay or prevent

the onset of cognitive decline and dementia.

Another approach is to decrease levels of Aβ

through immunological means. Both immunization

with Aβ, which leads to generation of antibodies to

Aβ, and passive transfer of Aβ antibodies have been

最小

最大

没有

阿尔茨海默病

阿尔兹海默

临床前期

非常轻度的

阿尔兹海默

轻度阿

尔兹海默

重度

阿尔

兹海默

中度阿尔

兹海默

淀粉斑

神经原纤维

缠结

神经元

完整性

Kandel-Ch64_1561-1582.indd 1577 19/01/21 9:22 AM

图 64.4.7: 生物标志物变化与阿尔茨海默病认知和临床变化的关系。在将要发展为阿尔茨海默病痴呆症的认知正

常人群中，最初的体征之一是 Aβ 以淀粉样蛋白斑块的形式在大脑中开始聚集。虽然人们的认知能力仍然正常，

但淀粉样斑块会继续积累。在某个时候，大约在任何明显的认知衰退发生前 5 年，tau 蛋白在新皮层中的积累开

始增加，炎症和氧化应激增加，大脑网络连接和新陈代谢开始下降。神经元和突触丢失以及脑萎缩也开始了。这

个时期（当患者保持认知正常但阿尔茨海默病型病理正在形成时）被称为临床前阿尔茨海默病。一旦有足够的

神经元和突触功能障碍以及细胞丢失，就会出现非常轻度的痴呆和轻度认知障碍。那时，淀粉样蛋白沉积几乎

达到顶峰。随着痴呆症恶化到轻度、中度和重度阶段，神经原纤维缠结形成，神经元和突触功能障碍、炎症、细

胞死亡和脑萎缩恶化

[564]

。

多年来，那些认为 Aβ 是阿尔茨海默病的主要致病因子的人和那些认为富含 tau 蛋白的缠结起主要作用的人

之间一直存在争议。这些坚定的支持者分别被称为浸礼宗和 Tau 信徒。浸礼宗指出，在症状出现前约 15 年开始

的阿尔茨海默病病理学发展过程中，新皮层 Aβ 的积累先于新皮层 tau 病理学的发展。然而，最近的证据表明，

Aβ 的积累似乎以某种方式驱动 tau 蛋白在大脑中聚集和扩散。因此，Aβ 聚集可能会引发疾病，而 tau 聚集和扩

散可能是导致神经变性的主要方式。例如，同时表达突变淀粉样前体蛋白和突变 tau 的转基因小鼠会出现更严重

的 tau 病理学。

斑块和缠结之间似乎存在相互作用。将 Aβ42 注射到表达突变 tau 蛋白的转基因小鼠的特定脑区会增加附近

神经元的缠结数量。此外，减少斑块数量和大小的操作会导致过度磷酸化 tau 水平降低。重要的是，最近的实验

表明，Aβ 沉积以某种方式促进 tau 聚集体从一个大脑区域扩散到另一个大脑区域，可能以类似朊病毒的方式跨

突触扩散。这一过程的细节仍有待制定，并且可能极其重要。

现在有大量来自细胞培养和动物模型研究的证据表明，在神经退行性疾病中聚集的几种蛋白质，包括 tau 和

突触核蛋白，可以以类似朊病毒的方式在细胞之间传播。这作为一种潜在的疾病机制尤为重要。例如，如果错误

折叠蛋白质的细胞间传播发生在细胞外空间，则该过程可能会被针对适当的疾病相关蛋白质的抗体打断。事实

上，这现在已成为多项针对 tau 和突触核蛋白的人体临床试验的基础。

64.4.3 已经确定了阿尔茨海默病的危险因素

极少数个体因携带淀粉样前体蛋白或早老素基因的常染色体显性突变等位基因而患上阿尔茨海默病，并且

这些通常属于早发型。几乎所有迟发性阿尔茨海默病病例都是由淀粉样前体蛋白或早老素基因突变引起的。那

么，我们可以预测这些人的阿尔茨海默病吗？

1391

64.5 现在可以很好地诊断阿尔茨海默病，但可用的治疗方法并不令人满意

主要的风险因素是年龄。这种疾病存在于 60 岁以下的极少数人群中（其中许多是常染色体显性遗传病例），

60 至 70 岁人群中的 1% 至 3%，70 至 80 岁人群中的 3% 至 12% , 以及 25% 到 40% 的 85 岁以上的老年人。然而，

知道老年人是阿尔茨海默病的主要候选人几乎没有治疗作用，因为现代医学无法减缓时间的流逝。因此，人们

对影响阿尔茨海默病发病率的其他因素产生了浓厚的兴趣。

迄今为止，发现的迟发性阿尔茨海默病最重要的遗传风险因素是载脂蛋白 E 基因的等位基因。ApoE 蛋白是

一种载脂蛋白。在血液中，它在血浆胆固醇代谢中起重要作用。它也在大脑中以高水平表达，最突出的是星形

胶质细胞，在一定程度上是小胶质细胞。在大脑中，其正常功能尚未阐明，它被分泌为高密度样脂蛋白的成分。

在人类中，载脂蛋白 E 基因有 3 个等位基因，载脂蛋白 E2、载脂蛋白 E3 和载脂蛋白 E4，它们之间至多相差

2 个氨基酸。携带载脂蛋白 E4 等位基因的人有患阿尔茨海默病的风险，而携带载脂蛋白 E2 等位基因的人相对

于具有最常见载脂蛋白 E3/载脂蛋白 E3 基因型的人而言可免受阿尔茨海默病的侵害。载脂蛋白 E4 等位基因存

在于大约 25% 的普通人群中，但存在于多达 60% 的阿尔茨海默病患者中。如图 64.4.8 所示，相对于载脂蛋白

E3/E3 的人，一个载脂蛋白 E4 等位基因拷贝增加阿尔茨海默病风险约 3.7 倍，2 个拷贝增加约 12 倍。相对于

APOE3/APOE3，一个载脂蛋白 E2 等位基因拷贝可将阿尔茨海默病风险降低约 40%。

Chapter 64 / The Aging Brain 1575

Figure 64–14 The risk for Alzheimer disease due to rare

and common genetic variants.Data are from genome-wide

association studies (GWAS). Mutations in the three genes that

cause early-onset familial Alzheimer disease (PSEN1, PSEN2,

and APP) are rare but result in Alzheimer disease in virtually

100% of people with these mutations if they live to middle

age. There have been a number of common genetic changes

found located in regions around or in genes that are relatively

frequent in the population (eg, ABCA7, CLU, BIN1) that affect

risk for Alzheimer disease but to a very small degree. The one

common and strong genetic risk factor for Alzheimer disease

that is present in about 20% to 25% of the population (allele

frequency ~15%) is APOE4. One copy of APOE4 increases risk

approximately 3.7-fold and two copies increase risk approxi-

mately 12-fold relative to people who are homozygous for

APOE3. (Adapted, with permission, from Karch and Goate 2015.)

The major risk factor is age. The disease is pre-

sent in a vanishingly small fraction of people younger

than age 60 (many of those being autosomal dominant

cases), 1% to 3% of those between ages 60 and 70, 3%

to 12% of those between ages 70 and 80, and 25% to

40% of those older than age 85. Knowing that elderly

people are prime candidates for AD is of little thera-

peutic use, however, because modern medicine can do

nothing to slow the passage of time. Therefore, there

has been intense interest in other factors that affect the

incidence of AD.

To date, the most significant genetic risk factors

discovered for late-onset AD are the alleles of the gene

APOE. The ApoE protein is an apolipoprotein. In the

blood, it plays an important role in plasma cholesterol

metabolism. It is also expressed at high levels in the

brain, most prominently by astrocytes and to some

extent by microglia. In the brain, where its normal func-

tion has not been clarified, it is secreted as a component

of high density-like lipoproteins. In humans, there are

three alleles of the APOE gene, APOE2, APOE3, and

APOE4, which differ from each other by at most two

amino acids. People with the APOE4 allele are at risk

for AD, whereas those with the APOE2 allele are pro-

tected against AD relative to people who have the most

common APOE3/APOE3 genotype. The APOE4 allele

is present in about 25% of the general population but

present in as many as 60% of those with AD. One copy

of the APOE4 allele increases the risk of AD by about

3.7-fold, and two copies by about 12-fold, relative to

someone who is ApoE3/E3 (Figure 64–14). One copy of

the APOE2 allele decreases the risk for AD by about

40% relative to being APOE3/APOE3.

The mechanism by which APOE4 predisposes to

AD and APOE2 protects against AD is uncertain, but

ApoE4 clearly promotes Aβ aggregation by diminish-

ing Aβ clearance and promoting fibrillization (ApoE4

> ApoE3 > ApoE2). It may also act through addi-

tional mechanisms such as influencing tau, the innate

immune system, cholesterol metabolism, or synap-

tic plasticity, although these pathways remain to be

worked out.

A number of other genes and genetic loci influ-

ence risk for late-onset AD. Some are common variants

that alter risk only slightly, whereas other rarer vari-

ants increase risk to a greater extent (Figure 64–14). For

example, relatively rare mutations in the gene TREM2

double or triple the risk for AD, similar to having one

copy of the APOE4 allele. This is interesting because

TREM2 as well as another gene associated with risk

少

群体中的频率 (%)

普通

14131211109876534 50403020

小

中

高

极高

（可能性

接近100%）

风险的相对增加

ADAM10

PSEN1

PSEN2

APP

APOE4

TREM2

PLD3

CD2AP

SORL1

DSG2

FERMT2

CASS4

INPP5D

PTK2B

PICALM

CR1

CLU

EPHA1

CELF1

CD33

RIN3

ABCA7

HLA

DRB5-1

SLC24A4

NME8

BIN1

MEF2C

MS4A

ZCWPW1

APP 新陈代谢

TAU 新陈代谢

胆固醇

免疫应答

内吞作用

细胞骨架/轴突发育

表观遗传学

未知

Kandel-Ch64_1561-1582.indd 1575 19/01/21 9:22 AM

图 64.4.8: 罕见和常见的基因变异导致阿尔茨海默病的风险。数据来自全基因组关联研究。导致早发性家族性阿

尔茨海默病（PSEN1、PSEN2 和淀粉样前体蛋白）的 3 个基因突变很少见，但如果他们活到中年，几乎 100% 的

携带这些突变的人都会患上阿尔茨海默病。在人群中相对频繁出现的基因（例如 ABCA7、CLU、BIN1）周围区域

或基因中发现了许多常见的遗传变化，这些变化影响阿尔茨海默病的风险，但影响程度非常小。载脂蛋白 E4 是

阿尔茨海默病的一种常见且强烈的遗传风险因素，存在于大约 20% 至 25% 的人口中（等位基因频率约为 15%）。

相对于载脂蛋白 E3 纯合子，一个载脂蛋白 E4 拷贝将风险增加约 3.7 倍，2 个拷贝将风险增加约 12 倍

[565]

。

载脂蛋白 E4 易患阿尔茨海默病而载脂蛋白 E2 预防阿尔茨海默病的机制尚不确定，但载脂蛋白 E4 通过减

少 Aβ 清除和促进原纤维化（载脂蛋白 E4 > 载脂蛋白 E3 > 载脂蛋白 E2）明显促进 Aβ 聚集。它还可能通过其

他机制发挥作用，例如影响 tau、先天免疫系统、胆固醇代谢或突触可塑性，尽管这些通路仍有待研究。

许多其他基因和基因位点影响迟发性阿尔茨海默病的风险。如图 64.4.8 所示，有些是仅轻微改变风险的常

见变体，而其他较罕见的变体会更大程度地增加风险。例如，TREM2 基因中相对罕见的突变使阿尔茨海默病的

风险增加 1 倍或 3 倍，类似于具有一个载脂蛋白 E4 等位基因拷贝。这很有趣，因为 TREM2 以及另一个与阿尔

茨海默病风险相关的基因 CD33 仅在小胶质细胞中表达。与其他新出现的细胞和动物模型数据一起，这一发现

表明先天免疫系统参与了阿尔茨海默病发病机制。正在研究其他一些在不同程度上增加风险的罕见变异。这些

发展似乎最终会导致更加个性化的临床方法来确定阿尔茨海默病的风险，特别是随着疾病治疗的出现。

1392

64.5 现在可以很好地诊断阿尔茨海默病，但可用的治疗方法并不令人满意

在缺乏生物标志物的情况下早期诊断阿尔茨海默病可能具有挑战性，因为它的初始症状可能与正常的年龄

相关认知衰退或其他相关疾病的症状相似。然而，阿尔茨海默病引起的轻度至中度痴呆的诊断通常相当准确。事

实上，在过去的几十年里，准确诊断疾病的能力有所提高，主要是因为 3 个因素。

首先，身体、神经和神经心理检查的规程变得更加复杂和标准化。其次，增加对核磁共振成像揭示的结构变

化的了解有助于早期诊断阿尔茨海默病。例如，现在可以根据核磁共振成像可见的皮层变薄和心室扩大来预测

哪些轻度认知损伤患者会发展为阿尔茨海默病，准确率约为 80%。这些成像和诊断方法还有助于区分痴呆综合

症，并将结构缺陷与功能缺陷联系起来。例如，患有被称为额颞痴呆行为变异的疾病的患者会在早期经历人格

改变，并且该阶段的核磁共振成像显示额叶和/或颞叶萎缩。同样，阿尔茨海默病最初的困难通常集中在记忆力

和注意力上，而核磁共振成像揭示了内侧颞叶皮层和海马体的初始改变。

第三，也许是最有前途的，淀粉样斑块和神经原纤维缠结可以通过正电子发射断层成像使用强烈结合纤维

状 Aβ 或聚集形式的 tau 的化合物进行可视化。如图 64.5.1 所示，其中第一个，匹兹堡化合物 B，以高亲和力结合

纤维状 Aβ；它的放射性形式，用短寿命的碳或氟同位素标记，很容易被正电子发射断层成像检测到。美国食品

和药物管理局已批准 3 种淀粉样蛋白显像剂：洛贝平（Amyvid）、富特米他（Vizamyl）和氟比他班（Neuraceq）。

1576 Part IX / Diseases of the Nervous System

Figure 64–15 Positron emission tomography

scans can visualize amyloid plaques in the

living brain.The density of Aβ plaques is indi-

cated by the red regions in these images made

after administration of Pittsburgh compound B

(PIB), a fluorescent analog of thioflavin T. (Images

reproduced, with permission, from R. Buckner.)

for AD, CD33, are expressed only in microglia. Along

with other emerging cellular and animal model data,

this finding suggests that the innate immune system is

involved in AD pathogenesis. A number of other rare

variants that increase risk to varying degrees are under

investigation. It seems likely that these developments

will ultimately result in a more personalized clinical

approach to determining risk for AD, especially as

treatments for the disease emerge.

Alzheimer Disease Can Now Be Diagnosed

Well but Available Treatments

Are Unsatisfactory

Diagnosing AD at its earliest stages in the absence of

biomarkers can be challenging, as its initial symptoms

can be similar to those of normal age-related cogni-

tive decline or of other related diseases. Nevertheless,

diagnosis of mild to moderate dementia due to AD is

usually fairly accurate. In fact, during the past few dec-

ades, the ability to accurately diagnose the disease has

improved, largely because of three factors.

First, protocols for physical, neurological, and

neuropsychological examination have become more

sophisticated and standardized. Second, increased

knowledge of the structural changes revealed by

magnetic resonance imaging (MRI) have helped in

diagnosing AD at early stages. For example, it is now

possible to predict, with approximately 80% accuracy,

which patients with MCI will develop AD based on

the cortical thinning and ventricular enlargement vis-

ible by MRI. These imaging and diagnostic methods

also assist in distinguishing dementia syndromes from

each other and relating structural to functional defects.

For example, patients with the disease known as

behavioral variant of frontotemporal dementia experience

personality changes early on, and MRI at that stage

reveals atrophy of the frontal and/or temporal lobes.

Likewise, initial difficulties in AD usually center on

memory and attention, and MRI reveals initial altera-

tions in the medial temporal cortex and hippocampus.

Third, and perhaps most promising, amyloid

plaques and neurofibrillary tangles can be visual-

ized by positron emission tomography (PET) using

compounds that avidly bind fibrillar forms of Aβ or

aggregated forms of tau. The first of these, Pittsburgh

compound B (PIB), binds with high affinity to fibrillar

Aβ; its radioactive form, labeled with short-lived iso-

topes of carbon or fluorine, is readily detected by PET

(Figure 64–15). The US Food and Drug Administration

(FDA) has approved three amyloid imaging agents:

florbetapir (Amyvid), flutemetamol (Vizamyl), and

florbetaben (Neuraceq).

The availability of safe molecular markers of AD

allows early stages of the disease to be identified before

clinical symptoms are present. Of equal importance,

it allows for improved selection of patients for clini-

cal trials and keener selection of subjects for detailed

analyses of normal aging. It is important to note that

these changes can also be detected in the cerebrospi-

nal fluid, where the level of Aβ42 drops when amyloid

deposition is present and total tau and phosphorylated

forms of tau increase with neurodegeneration and tau

aggregation.

Of course, improved diagnosis of AD is most use-

ful if treatments are available that can halt or slow its

progression at an early stage. While we still do not

正常阿尔兹海默病

Kandel-Ch64_1561-1582.indd 1576 19/01/21 9:22 AM

图 64.5.1: 正电子发射断层扫描可以显示活体大脑中的淀粉样斑块。Aβ 斑块的密度由这些图像中的红色区域表

示，这些图像是在施用匹兹堡化合物 B 后制作的，这是一种硫黄素 T 的荧光类似物。

阿尔茨海默病安全分子标记的可用性允许在出现临床症状之前识别疾病的早期阶段。同样重要的是，它可

以改进临床试验患者的选择，以及更敏锐地选择受试者以进行正常衰老的详细分析。重要的是要注意，这些变

化也可以在脑脊液中检测到，当存在淀粉样蛋白沉积时，

的水平会下降，总

tau

和磷酸化形式的

tau

会随

着神经变性和 tau 聚集而增加。

当然，如果有可以在早期阶段阻止或减缓其进展的可用治疗方法，改进阿尔茨海默病的诊断将是最有价值

的。虽然我们仍然没有延迟阿尔茨海默病发作或减缓阿尔茨海默病进展的治疗方法，但希望我们离能够减轻症

状不会太远。虽然没有明确的证据，但有充分的证据表明各种生活方式因素可以降低患阿尔茨海默病的风险。这

些包括高水平的教育、认知刺激、保持社交参与、定期锻炼、不超重以及获得适量的睡眠。目前的疗法侧重于治

疗相关症状，例如抑郁、情绪激动、睡眠障碍、幻觉和妄想。

迄今为止，治疗的一个主要目标是针对基底前脑中的胆碱能系统，这是一个在阿尔茨海默病中受损并有助

于注意力的大脑区域。乙酰胆碱酯酶抑制剂通过抑制乙酰胆碱的分解来提高乙酰胆碱的水平，是美国食品和药

物管理局批准用于治疗阿尔茨海默病的少数几种药物之一。另一种药物 N-甲基-D-天冬氨酸受体拮抗剂美金刚也

可改善因阿尔茨海默病导致的轻度至中度痴呆患者的症状。美金刚被认为能够调节谷氨酸介导的神经传递。然

而，这些药物对改善认知功能和日常生活活动的影响并不大。

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64.5 现在可以很好地诊断阿尔茨海默病，但可用的治疗方法并不令人满意

我们对阿尔茨海默病细胞生物学基础理解的最新进展产生了几个有希望的新治疗靶点，所有这些靶点都在

深入探索中。一种方法是开发降低或调节 β- 和 γ- 分泌酶活性的药物，这些酶切割淀粉样前体蛋白以产生 Aβ 肽

和相关的可溶性细胞外片段和细胞内片段。事实上，降低过表达突变淀粉样前体蛋白的转基因小鼠中的 β- 或 γ-

分泌酶水平会减少 Aβ 沉积，并且在某些情况下会减少功能异常。

因此，制药公司开发了降低或调节人体 β- 和 γ- 分泌酶水平的药物。这种方法的一个障碍是分泌酶还作用

于淀粉样前体蛋白以外的底物，因此降低它们的水平可能会产生有害的副作用。对于 γ-分泌酶尤其如此，其抑

制作用已导致阿尔茨海默病人体试验中的毒性。如图 64.4.7 所示，现在有几种 β-分泌酶抑制剂在阿尔茨海默病

的临床试验中，这些药物很可能也会进入所谓的临床前阿尔茨海默病试验，此时阿尔茨海默病病理正在积累但

还没有认知衰退的迹象。这种疗法的目标是延缓或预防认知能力下降和痴呆症的发生。

另一种方法是通过免疫学手段降低 Aβ 水平。导致产生 Aβ 抗体的 Aβ 免疫和 Aβ 抗体的被动转移都已在阿

尔茨海默病的转基因小鼠模型中进行了测试。如图 64.5.2 所示，2 种治疗均已显示可降低 Aβ 水平、Aβ 毒性和

斑块。增强 Aβ 清除的机制尚不完全清楚。血清抗体可能起到“接收器”的作用，导致低分子量的 Aβ 肽从大脑

中更广泛地清除到循环中，从而改变不同隔室中 Aβ 的平衡并促进 Aβ 从大脑中去除。

1578 Part IX / Diseases of the Nervous System

Figure 64–17 Immunization with antibodies to the Aβ

peptide clears amyloid plaques and preserves cognitive

performance in mice expressing the peptide.Mice that

develop Aβ deposition in the form of amyloid plaques were

immunized with the Aβ peptide. This led to production of anti-

bodies against Aβ.

A.Comparison of amyloid plaque deposition in the cerebral

cortex of mice overexpressing a mutant APP transgene (APP

transgenic mice) that develop amyloid plaques. The mice

that were immunized with the Aβ peptide have substantially

reduced amyloid plaque deposition. (Adapted from Brody and

Holtzman 2008.)

B.Cognitive performance (a memory test) in two groups of APP

transgenic mice. One group was immunized with an irrelevant

protein, the other with the Aβ peptide. The mice vaccinated with

Aβ performed at levels close to normal animals, whereas mice

immunized with the irrelevant protein showed severe impairment

in memory. (Adapted, with permission, from Janus et al. 2000.)

tested in transgenic mouse models of AD. Both treat-

ments have been shown to reduce levels of Aβ, Aβ

toxicity, and plaques (Figure 64–17). The mechanisms

of enhanced Aβ clearance are not completely clear.

Serum antibodies likely serve as a “sink,” resulting in

Aβ peptides with low molecular weight being cleared

more extensively from the brain into the circulation,

thus changing the equilibrium of Aβ in different com-

partments and promoting removal of Aβ from the

brain.

It is also clear that in the brain several anti-Aβ

antibodies bind either soluble or fibrillar Aβ, or both.

Those that bind to aggregated forms of Aβ can stim-

ulate microglia-mediated phagocytosis to remove

Aβ, although there is also plaque removal that is not

dependent on microglial-mediated phagocytosis. Anti-

bodies to soluble Aβ that enter the brain may decrease

soluble Aβ toxicity. These findings suggest that immu-

notherapeutic strategies may be successful in AD

patients, especially if they are given early enough in the

disease course, prior to significant neuronal damage

and loss. There are multiple human trials underway

using active and passive immunotherapies against Aβ

both in preclinical and mild AD.

用无关蛋白免疫小鼠

用

Aβ 1-42 免疫的小鼠

任务延迟（秒）

12345

试验次数

B 记忆任务

正常老鼠

淀粉样前体蛋

白转基因老鼠

A 淀粉样斑块沉积

淀粉样前体蛋白转基因小鼠的皮层

突变淀粉样前体蛋白

转基因小鼠 Aβ 1-42 免疫后的皮层

Kandel-Ch64_1561-1582.indd 1578 19/01/21 9:22 AM

图 64.5.2: 用 Aβ 肽抗体进行免疫可清除淀粉样斑块并保持表达该肽的小鼠认知能力。用 Aβ 肽免疫以淀粉样斑

块形式形成 Aβ 沉积的小鼠。这导致了针对 Aβ 的抗体的产生。A. 过表达突变淀粉样前体蛋白转基因小鼠的大脑

皮层淀粉样斑块沉积的比较，该小鼠会形成淀粉样斑块。用 Aβ 肽免疫的小鼠淀粉样斑块沉积显著减少

[566]

。B.

两组淀粉样前体蛋白转基因小鼠的认知表现（记忆测试）。一组用无关蛋白免疫，另一组用 Aβ 肽免疫。接种 Aβ

的小鼠的表现水平接近正常动物，而接种无关蛋白的小鼠则表现出严重的记忆障碍

[567]

。

同样清楚的是，在大脑中，几种抗 Aβ 抗体结合可溶性或纤维状 Aβ，或两者结合。那些与聚集形式的 Aβ

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64.6 亮点

结合的物质可以刺激小胶质细胞介导的吞噬作用以去除 Aβ，尽管也有不依赖于小胶质细胞介导的吞噬作用的斑

块去除。进入大脑的可溶性 Aβ 抗体可能会降低可溶性 Aβ 的毒性。这些发现表明，免疫治疗策略可能在阿尔茨

海默病患者中取得成功，特别是在疾病过程中、在出现严重神经元损伤和丢失之前尽早进行治疗。在临床前和

轻度阿尔茨海默病中，正在进行多项针对 Aβ 的主动和被动免疫疗法的人体试验。

除了针对 Aβ，临床试验也开始针对 tau。这是通过针对 tau 的主动和被动免疫以及在细胞培养和动物模型中

可以减少 tau 聚集的小分子来完成的。许多动物模型研究表明，某些抗 tau 抗体可以减少中枢神经系统中聚集的、

过度磷酸化的 tau 蛋白的数量，并在某些情况下改善功能。虽然 tau 主要是一种细胞质蛋白，但抗 tau 抗体可能

起作用的原因之一是，如上所述，tau 聚集体可能以类似朊病毒的方式在细胞外空间中从一个细胞扩散到另一个

细胞。正是在这个空间中，抗体可能能够与 tau 相互作用并阻断这个过程。

64.6 亮点

1. 只是在过去的 50 年里，许多人能够活到活到 80 岁甚至更久。随着寿命的增加，神经科学家有机会深入

研究正常衰老过程中的变化以及患有与年龄相关的脑部疾病的个体的大脑变化。

2. 随着年龄的增长，人脑的多种功能会发生微妙的变化，包括处理速度和记忆存储的下降以及睡眠的变化。

这些变化的根本原因可能是脑萎缩和白质完整性丧失。然而，总的来说，神经元数量并没有显著减少，这有助于

我们理解在正常衰老过程中大脑功能变化的原因。

3. 正常衰老过程中发生的认知变化不会致残。当记忆力和认知功能的其他区域随着年龄的增长而下降超出

正常老化的预期，以至于其他人会注意到并轻度影响一个人的日常生活时，这种综合症称为轻度认知损伤。

4. 轻度认知损伤不是一种疾病，它是一种综合症。大约 50% 的轻度认知损伤患者将阿尔茨海默病作为轻度

认知损伤的根本原因。其他可能导致轻度认知损伤的情况包括抑郁症、脑血管疾病、路易体病、代谢紊乱，以及

针对其他疾病开出的会引起中枢神经系统副作用的药物。

5. 阿尔茨海默病是痴呆症最常见的原因，表现为记忆力和其他足以损害社会和职业功能的认知能力丧失。

在美国，阿尔茨海默病约占痴呆病例的 70%，其余主要由脑血管疾病、帕金森和路易体痴呆以及额颞痴呆引起。

6. 阿尔茨海默病的病理学特征是 2 种蛋白质 Aβ 肽和 tau 的聚集形式在大脑中的积累。Aβ 以纤维状形式积

聚在脑实质和小动脉壁（称为脑淀粉样血管病）中的称为淀粉样斑块的细胞外结构中。Tau 在细胞体和树突中的

神经原纤维缠结中积累。

7. 在阿尔茨海默病中，除了大脑内蛋白质聚集体的累积外，随着疾病的进展，还会出现明显的脑萎缩以及突

触和神经元丢失。还有强烈的神经炎症反应，特别是在小胶质细胞和星形胶质细胞的淀粉样斑块周围表现明显。

8. 阿尔茨海默病的病理学在认知衰退或疾病的轻度认知损伤阶段之前约 15 年就开始了。新皮层中的 Aβ 积

聚似乎以明显异常的水平引发疾病，随后 tau 聚集体从内侧颞叶扩散到新皮层的其他区域。症状出现之前的阿尔

茨海默病病理学阶段称为临床前阿尔茨海默病。

9. 重要数据表明，Aβ 肽的某些聚集形式会导致阿尔茨海默病大脑中的突触和神经元损伤，但与认知能力下

降更好相关的是 tau 蛋白聚集形式的存在和积累。

10. 阿尔茨海默病有 2 种主要形式。第一种是显性遗传性阿尔茨海默病（占阿尔茨海默病患者的比例不到

1%）是由编码蛋白质淀粉样前体蛋白、PS1 和 PS2 的 3 个基因之一的突变引起的；这种形式导致临床疾病在 30

到 50 岁之间发作。遗传、生物化学和其他研究表明，导致常染色体显性阿尔茨海默病的基因通过 Aβ 肽在大脑

中的早期积累来实现。第二种形式，迟发性阿尔茨海默病，发病年龄为 65 岁或更晚，占病例的 99% 以上。虽然

年龄是迟发性阿尔茨海默病的最大危险因素，但遗传因素也有影响。载脂蛋白 E 基因是迄今为止阿尔茨海默病

的最大遗传因素，载脂蛋白 E4 变体增加风险，载脂蛋白 E2 变体降低风险。影响风险的其他基因中还有许多其

他常见的遗传变异。其他基因（如 TREM2）中也存在罕见变异，这些变异将风险增加到与载脂蛋白 E4 一个拷

贝相关的水平。尽管如此，普遍认为散发性和家族性阿尔茨海默病发病机制的主要特征相似。

11. 除了阿尔茨海默病的临床症状和体征外，淀粉样蛋白和 tau 成像以及脑脊液标记物可以确定活人是否存

在认知衰退的阿尔茨海默病症。

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64.6 亮点

12. 目前，对于阿尔茨海默病，我们仅有的治疗方案主要是对症治疗，其效果只能带来适度的益处。许多影

响 Aβ 或 tau 的产生、清除和聚集的潜在疾病缓解疗法正在人体中进行测试。尽管这些疗法尚未获得批准，但希

望在未来几年内，其中一种或多种疗法能够证明具有显著的治疗效果。

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